JPS6055068B2 - 1-(3-halo-2-pyridinyl)piperazine - Google Patents

Abstract

1-(3-Halo-2-pyridinyl)piperazine and its acid addition salts are selective alpha 2-adrenergic receptor antagonists and thereby useful as antidepressant agents and for treating sedation caused by antihypertensive therapy.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel 1-(3-hacar-2-pyridinyl)piperazine and its pharmaceutically acceptable salts having the ability to inhibit antidepressant activity and sedative side effects of antihypertensive agents. It is something.

The invention further relates to methods for preparing these novel compounds and to pharmaceutical compositions comprising the novel compounds. Piperazinyl compounds are particularly common among compounds with useful pharmacological properties. Piperazinylpyrazine (U.S. Pat. Nos. 4,081,542 and 408,284)
No. 4) Piperazinylquinoxaline (French Patent No. 22)
3649 hours) and 2-piperazinyl-5 (and/or 6
) Monosubstituted pyridines (US Pat. No. 4,078,063) are known as anorexigenic substances. These substances are also said to have anti-depressant activity due to their pharmacological influence on serotonin levels. At this point,
The present invention provides 1-(3-halo2-pyridinyl)piperazine. This substance is an antidepressant and α
Because of their ability to selectively antagonize 2-adrenergic receptor sites, they have activity in blocking the sedative effects of antihypertensive drugs. It is now widely accepted that the complex clinical stages of sedation are related to functional deficiencies of monoamines in the central nervous system.

A number of biochemical and clinical observations support the proposal that many forms of sedative disease are associated with decreased adrenergic activity in functionally important areas of the brain.
For example, classical antidepressants such as amitriptyline and imipramine act to block neuronal reuptake of norepinephrine and/or serotonin, thereby enhancing the ability of monoamines as neurotransmitters. It is believed that The combination of a norepinephrine reuptake blocker and a selective α2-adrenergic receptor antagonist, although their effects are at least additive, forms another aspect of the invention.

In addition to the α1-adrenergic receptors that mediate the post-synaptic response to the neurotransmitter norepinephrine, other adrenergic receptors are present at or near sympathetic nerve terminals.

These latter receptors, α2-adrenergic receptors, are a negative feedback system that modulates noradrenergic neurotransmission by suppressing the shock-induced release of norepinephrine from presynaptic terminals. forms part of. Activation of α2-adrenergic receptors reduces the amount of norepinephrine released from nerve terminals normally upon nerve impulse, whereas antagonism of α2-adrenergic receptors increases norepinephrine release. . Molecules that block α2-adrenergic receptors therefore provide another means for improving noradrenergic function and treating sedation associated with absolute or relative deficiency of adrenergic function. Mianserin, a clinically effective antidepressant that has been reported to have minimal properties of inhibiting norepinephrine reabsorption in vivo, blocks α2-adrenergic receptors.

However, mianserin fails to exhibit any significant selectivity for α1- or α2-adrenergic receptors. This means that mianserin is α2 in vivo.
This suggests that α1 receptors are blocked in an amount approximately equal to the amount S required to block α1 receptors (
CIirleschmidt et al., Arch. Int.
PharmacOdyTl. Ther. 242,59(
1979)). The compounds of the invention are highly selective for α2-adrenergic receptors, and the less selective α1
,, has distinct therapeutic advantages compared to α2 monoantagonists. α1 (or post-synaptic) blockade
Compounds that selectively antagonize α2-adrenergic receptors induce an increase in neurotransmission at noradrenergic synapses because they interfere with the increase in noradrenergic transmission initiated by blockade. Furthermore, molecules with reduced α,1-receptor blocking properties, such as compounds of the invention, may be
It is less likely to cause orthostatic hypotension, which is an undesirable side effect (Syrlder, PharmakOpsy
chiatl3, 62 (1980)). The limited side effects of sedation caused by certain antihypertensive agents are believed to be related to stimulation of presynaptic α2-adrenergic receptors.

However, the reduction in blood pressure caused by these antihypertensive agents is not related to these receptors, but rather to post-synaptic adrenergic receptors (Birch et al., Br.
．． J. PhamlacOl. 68, lO7P (1979
)). Selective α2-receptor antagonists should be useful in reducing the adverse effects of sedation induced by certain antihypertensive agents. For example, the selective α2-receptor blocker yohimpine suppresses the sedation caused by clonidine.
Drew et al., Br. J. PharmaOl. 67, l
33 (1979)) and the motor sedative effect of methyldopa in mice (Cllrleschmidt et al., Ar.
Ch. Int. PharmacOdyTl. Ther.
, 244, 23l (1980)). Furthermore, yohimpine has been reported to reduce clonidine-induced sedation in humans (Autret et al., Eur. J. Clln. PharmacOl.l2,
3l9 (1977)). The compounds of the invention are highly selective for α2-adrenergic receptors and efficiently reduce the sedative effects of antihypertensive drugs without affecting their hypotensive effects. The present invention relates to 1-(3-halo2-pyridinyl)piperazine or a pharmaceutically acceptable salt thereof. Halo here refers to chlorine, bromine, or fluorine, especially fluorine. Pharmaceutically acceptable salts falling within the scope of this invention include pharmaceutically acceptable acid monoaddition salts.

Acids useful in the preparation of these acid monoaddition salts include, among others, hydrohalic acids (e.g. hydrochloric acid and hydrobromic acid), inorganic acids such as sulfuric acid, nitric acid and phosphoric acid, maleic acid, fumaric acid, tartaric acid, Citric acid, acetic acid, benzoic acid, 2-acetoxybenzoic acid, salicylic acid, succinic acid, theophylline, 8
- Organic acids such as chlorotheophylline, p-aminobenzoic acid, p-acetamidobenzoic acid, methanesulfonic acid or ethanedisulfonic acid. The novel compounds of the present invention are prepared by the reaction of 2-Y-3-halopyridine of formula 1 with piperazine of formula 2.

The reaction sequence is as follows: where Y is halogen, especially chlorine, C1-5 alkylsulfonyloxy such as methanesulfonyloxy; or arylsulfonyloxy such as benzenesulfonyloxy or toluenesulfonyloxy; C1-5 alkylsulfonyloxy; benzenoid arylsulfonyl such as benzenesulfonyl or toluenesulfonyl, and R is -H or 8.

R1 is hydrogen, C1-3 alkyl, benzenoid aryl such as phenyl, tolyl, xylyl, benzenoid aryloxy such as C1-3 alkoxy, phenoxy, tolyloxy, xylyloxy, or -NR2R3 (R2 and R3 are independently hydrogen or C1 -3 alkyl, or R2 and R3 together form tetramethylene, pentamethylene or 1(CH2)20(CH2)2-). Step A is typically carried out at temperatures ranging from room temperature to about 200° C., preferably under an inert atmosphere, such as N2, He or Arl, until a large amount of the desired compound of formula (I) is obtained. This is carried out for a period of about 0.25 to about 5 days, preferably about 0.5 to about 3 days.

This reaction is carried out in the absence of solvent or in the presence of an inert organic solvent such as a C2-5 alkanol, preferably butanol, acetonitrile, dimethylformamide or dimethylsulfoxide.

For step B, acidic or basic hydrolysis conditions are used.

For basic hydrolysis, alkali metal hydroxides such as KOH and NaOH are preferred. At least 2 molar equivalents of base are required for best results, but an excess of 2-10 equivalents is preferred. As a solvent, H2O can be used, but it is also possible to add a co-solvent that is miscible with water, such as methanol, ethanol, ethylene glycol or DMF. The hydrolysis is carried out at a temperature ranging from about room temperature to about 200°C, preferably under an inert atmosphere of N2, He or A, typically for about 1 hour to about 2 days, preferably about 3 hours to 1 hour. Do it for days. For acid hydrolysis, dilute or concentrated aqueous mineral acids such as HCI or HBrl
Or diluted or concentrated sulfuric acid is preferred.

It is possible to add water-miscible organic solvents such as ethanol, acetic acid, ethylene glycol, etc. Reaction temperatures range from about room temperature to about 150°C, with an inert atmosphere being preferred. A reaction time of about 1 hour to 2 days is required, preferably 3 hours to 1 day. Another method consists of removing the N1'' alkyl, alkenyl or aralkyl group from the piperazine nitrogen.

These groups can be synthesized in an anhydrous aprotic solvent such as ether, chloroform, toluene or benzene at a temperature between 0° C. and the boiling point of the solvent to form one equivalent of the cyatogenic promide, cycloalkoxyhalide, or Carbohaloalkoxyhalide, Carboalkenoxyhalide,
Removal by reaction with a carboaryloxy halide or a carboarylalkoxy halide provides a compound of structure (1).

In the formula, R2 is -CN or
1-3 alkyl, haloC1-3 alkyl, vinyl or 1
- C2-4 alkenyl such as propenyl, benzenoid aryl such as phenyl, or benzenoid aryl C1-3 alkyl such as phenyl-C1-3 alkyl.

These groups R2 are then removed by acid or alkaline hydrolysis similar to that described for the hydrolysis of substituent 1-1. Some of the carbamates (2) are converted to secondary amines by other methods.

For example, β, β, β-trichloroethyl carbamate (
CCl, CH9 product-N/) was prepared by heating with excess zinc dust in C1-3 alkanol or aqueous acetic acid.
It is converted to a secondary amine.

alkenyl carbamate (e.g. 0H2.H4, -N2 is anhydrous HCl in C1-3 alkanol, or HBrl in acetic acid or Hg in acetic acid water)
It is removed by treatment with (0Ac)2.

A preferred dealkylation method is to convert the tertiary amine into an ether, C
Phosgene (C
OCl2) and then reacted with vigorous stirring for about 25 min.
C. to about 100.degree. C., add excess water and process for 1 to 1 hour.

In the case of N-benzyl derivatives, aralkylation can be carried out by all the methods mentioned above and by Pd, . pt,. It can be removed by hydrogenation in a solvent such as alcohol, acetic acid, or H2O using a ptO2 or Raney Nickel catalyst under about 1 atmosphere to about 5 leakage pressure for 3 hours to 1 day.

Another method is described below and comprises the reduction of pyridine-N-oxide, suitable reducing agents being sulfur dioxide, triphenylphosphine, in tin, zinc, Fe or inorganic or organic acids. This is catalytic hydrogenation using sodium arsenite, ferrous oxalate, granulated lead, palladium on carbon, Raney nickel, and the like.

Suitable solvents include polar solvents such as water, acetic acid, lower alcohols, and the like. The reaction is carried out at a temperature of about 0°C to about 150°C. Another method consists of forming a piperazine ring as follows. In the formula, X is the same or different and is a substitutable group such as halogen, tosyloxy, mesyloxy, or trialkylammonium.

Generally, the above reaction is carried out by mixing the reaction reagents in a polar solvent such as water, dimethylformamide, alcohol, etc. from about 0°C to about 25°C (
The process proceeds by heating to a certain temperature. α2 in patients
- In this novel method of selectively antagonizing adrenaline 7 receptors, the novel compound or a pharmaceutically acceptable salt thereof is administered from about 0.01 to about 20 m9 per k9 body weight per day, preferably from about 0.01 m9 to about 20 m9 per k9 body weight per day. about 0
．． Amounts ranging from 1 to about 10 m9 may be administered in a single dose or in 2 to 4 divided doses. These medications are useful in treating the depression or sedation caused by antihypertensive therapy.

When used in combination with a norepinephrine reuptake blocker antisedative, it is recommended that the dose of each drug be halved.

For administration as described above, the compounds of the invention or pharmaceutically acceptable salts thereof are administered orally, intraperitoneally, subcutaneously, intravenously or intramuscularly.

The above-mentioned drugs may be administered orally, such as in tablets, troches, capsules, bolus, suspensions, syrups, wafers, chewing gum, or other forms prepared by any art-recognized method. is preferred. The amount of active compound in such therapeutically useful compositions or preparations is adjusted so that a suitable dosage will be obtained. The toxicity test results of the compounds according to the present invention are shown below. Compound: 1-(3-fluoro-2-pyridinyl)piperazine dihydrochloride Experimental animal: Mouse CF-1 Sex: Female Administration route: Oral Vehicle: Distilled water for injection Calculated LD5O: 313 (282-349) M9 /K9l
Activity decreases within 2200m for all doses
For doses above 9/K9, ataxia occurred within 4 doses.
Tremors and tonic convulsions were observed; death occurred between 48 and 2 months after 61 days [Notes] All doses were calculated for the compound as a whole.

Example 11 - (3-Fluoro-2-pyridinyl)piperazine dihydrochloride Preparation of 2-chloro-3-fluoropyridine (500 m9, 4.25 mmol) and anhydrous piperazine (3.66 g142.5 mmol) in 40 m1 of n-butanol. Stir the solution for 1 FR with stirring.

After concentration to dryness in vacuo, the residue is partitioned between toluene and dilute caustic soda solution (5% W/V). The toluene phase was washed with saturated brine, dried over Nα2S04, and concentrated to 0.
．． Use 65g of oil. This oil was treated with ethanolic hydrogen chloride and the crude material was dissolved in a minimum amount of methanol diethanol (1
:1) Dissolve in a mixed solution and crystallize by adding ethyl acetate to create turbidity, 0.3 kg (35% yield)
A product with a melting point of 203-210°C is obtained. Calculated value: Ca
Hl2FN3●2HC1:C, 42.53; H, 5.5
5; N, l6.53 Actual value: C, 42. l6:H,5.
64;N,l 6.39 By substantially the same method as described in Example 1, an equimolar amount of 3-bromo 2-chloro. 1-(3-bromo-2-pyridyl)piperazine hydrochloride, melting point 180°C (decomposed) and 1-(
3-chloro-2-pyridyl)piperazine hydrochloride, melting point 1
42-144°C is produced.

) Example 21-(3-fluoro-2-pyridinyl)piperazine dihydrochloride Step A: Preparation of 1-(3-fluoro-2-pyridinyl)-14-carboethoxy piperazine 2-chloro3 in 60 ml of n-butanol
-Fluoropyridine (650m9, 5.06 mmol)
and ethyl N-piperazinocarboxylate (1.61 g
110.2 mmol) while stirring the solution under nitrogen.
reflux for an hour).

After concentration to dryness under reduced pressure, the residue is dissolved in a mixture of ethyl acetate and water. The ethyl acetate phase is washed again with water, dried over anhydrous sodium sulfate, filtered and concentrated. The N-carboethoxy derivative of 1-(3-fluoro-2-pyridinyl)piperazine is further purified by chromatography on silica gel 60 (230-400 mesh).

Step B: Preparation of 1-(3-fluoro-2-pyridinyl)piperazine dihydrochloride 50ml? 1-(3 in hydrochloric acid
-fluoro-2-pyridinyl)-4-carboethoxypiperazine solution is refluxed with stirring under N2 for 6 hours.

Recrystallization of the residue from ethanol-ethyl acetate yields 1-
(3-Fluoro-2-pyridinyl)piperazine dihydrochloride is obtained. Example 3 1-(3-fluoro-2-pyridinyl)piperazine hydrogen maleate Step A: Preparation of 1-(3-fluoro-2-pyridinyl)-4-formylpiperazine 40ml
A solution of 2-chloro-3-fluoropyridine (500 m9, 4.25 mmol) and 1-piperazine carboxaldehyde (970 m9, 8.50 mmol) in n-butanol is stirred under nitrogen for 18 hours.

After concentration to dryness in vacuo, the residue is partitioned between toluene and water. The toluene extract was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated to an oil. The N-formyl derivative is purified by chromatography on silica gel 60 (230-400 mesh). Stage B:1
-(3-fluoro2-pyridinyl)piperazine
Preparation of hydrogen maleate salt 1-(3
-fluoro2-pyridinyl)-4-formylpiperazine solution is refluxed under nitrogen for 1 hour with stirring.

After removing most of the ethanol under reduced pressure at 40-450°C, the organic product is extracted with toluene. This toluene extract was washed with saturated brine, dried over anhydrous sodium sulfate, filtered through p-filter, and concentrated to an oil. child. oil is dissolved in ethanol, treated with an equivalent amount of maleic acid, and ethyl acetate is added to give 1-(3-fluoro-2-pyridinyl).
The hydrogen maleate salt of piperazine precipitates. 1-(3-
Fluoro-2-pyridinyl)pipera zine hydrogen maleate has a melting point of 165-166°C.

Example 4 1-(3-fluoro-2-pyridinyl)piperazine hydrogen maleate Step A: Preparation of 1-methyl-4-(3-fluoro-2-pyridinyl)piperazine 50ml
A solution of 2-chloro-3-fluoropyridine (1.0 g 1 & 5 mmol) and N-methylpiperazine in n-butanol is refluxed with stirring for 1a.

After concentration under reduced pressure at 50° C., the residue is partitioned between ethyl ether and 5.0% NaOH solution. The ethyl acetate phase is washed with saturated brine, dried over Nα2SO, filtered and concentrated under reduced pressure. The oily product is converted to the hydrogen fumarate salt, mp 148-149'C, by treatment with fumaric acid in methanol and precipitation with ethyl ether. Step B: 1-(3-fluoro-2-pyridinyl)
Piperazine hydrogen maleate 1-methyl-4-(3-fluoro-2-pyridinyl) in 25 ml of toluene
Piperazine (a). 98g,. 5.0 mmol) 3.96 g of phosgene in a 12.5% solution in toluene are added to the solution while cooling it in an ice bath.

After stirring for 1 hour at 5-10°C, the mixture was heated to 20-2
Return to 5℃ and keep at this temperature for 3 days.

Then 10ml of water was added and the mixture was stirred vigorously at 50°C for 6
Stir for an hour. The aqueous phase is removed, made basic with 10% NaOH solution and the product is extracted with ethyl acetate. The ethyl acetate extract was washed with saturated NaCl-H2O solution, dried over anhydrous sodium sulfate, filtered, and concentrated to an oil. This oil is dissolved in ethanol, treated with an equivalent amount of maleic acid, and ethyl acetate is added to precipitate hydrogen maleate. Example 5 1-(3-fluoro-2-pyridinyl)piperazine dihydrochloride Step A: 1-benzy-4-(3-fluoro-2-pyridinyl)piperazine dihydrochloride
Preparation of -pyridinyl)piperazine dihydrochloride A solution of 2-chloro-3-fluoropyridine (1.0 g, 18.05 mmol) and N-benzylpiperazine (3.0 g, .17 mmol) in 50 ml of n-butanol was stirred. The water is refluxed for 2 hours.

After concentration under reduced pressure at 5σC, the residue is partitioned between ethyl acetate and 5% sodium hydroxide solution. The toluene phase was washed with saturated saline, dried over anhydrous sodium sulfate, filtered,
Concentrate into oil. Treatment of this oil with ethanolic hydrogen chloride and recrystallization from an ethanol-ethyl acetate mixture yields 1-benzy-4-(3-fluoro-2-pyridinyl).
The dihydrochloride of piperazine is obtained. Stage B: 1-(3-
Preparation of 1-benzy-4-(3-fluoro-2-pyridinyl)piperazine dihydrochloride (500
m9, 1.8 mmol) solution was shaken at 50 °C with 100 mg of platinum oxide catalyst in a hydrogen atmosphere of 2 atm,
The reaction is carried out until an equivalent amount of hydrogen is absorbed.

The catalyst is removed and the bottom liquid is concentrated under reduced pressure. The residue is recrystallized from an ethanol-ethyl acetate mixture to obtain 1-(3-fluoro-2-pyridinyl)piperazine dihydrochloride. Example 6 1-(3-fluoro-2-pyridinyl)piperazine dihydrochloride Step A: 2-chloro-3-fluoropyridine N
- Preparation of the oxide A mixture of 2-chloro-3-fluoropyridine (11.8 g 10.10 mol) and 11.4 ml of 30% hydrogen peroxide in 70 ml of glacial acetic acid was prepared at 75°C.
Stir for an hour.

A further 3×5 ml of 30% hydrogen peroxide are added over 2S, followed by 3 ml of saturated sodium sulfite solution. The reaction mixture was concentrated under reduced pressure at 55-60 DEG C. to about 25 ml, diluted with 30 ml of water and made basic with potassium carbonate. The crude N-oxide is extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Chromatography on silica gel (270M
2 by e0H-98% CHCl3 (V/■) mixture)
-Chloro-3-fluoropyridine N-oxide is obtained as a liquid. Step B: 2-(1-piperazinyl)-3
- Fluoropyridine N-oxide A solution of 2-chloro3-fluoropyridine N-oxide (400 TrLg, 3.0 mmol) and piperazine (1.3 g, 115 mmol) in 15 ml of n-butanol is refluxed for an hour with stirring. .

After concentration under reduced pressure at 55-60 C with stirring, the residue is chromatographed on silica gel and the crude N-oxide is eluted with a 50% methanol-methylene chloride mixed solvent. Concentration of the appropriate eluate fraction provides the title compound as an oily residue. Step C: 1-(3-fluoro-2-pyridinyl)
Preparation of piperazine dihydrochloride 3 in 10 ml glacial acetic acid
- Fluoro-2-pyridinyl pyridine N-oxide solution is heated to about 85°C and saturated with anhydrous hydrogen chloride gas,
Treat for 1 hour while slowly flowing sulfur dioxide.

The acetic acid is removed under reduced pressure and the residue is crystallized from an ethanol-ethyl acetate mixture to give the title compound. Example 7 1-(3-fluoro-2-pyridinyl)piperazine hydrogen maleate Step A: 2-[N,N-bis(2-hydroxyethyl)amino]-3-fluoropyridine
Preparation of 2-chloro3 in 50 ml n-butanol
- A solution of fluoropyridine (1.0 g 18.5 mmol) and diethanolamine (2.1 g 120 mmol) is refluxed for 2 hours with stirring under nitrogen.

After removing most of the n-butanol under reduced pressure at about 50'C, the residue is partitioned between ethyl acetate and 5% sodium hydroxide solution. The ethyl acetate phase is washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue is purified by chromatography on silica gel 60 (230-400 mesh) to yield 2-[N,N-bis(2-hydroxyethyl)amino]-3-fluoropyridine. Step B: 2-[N,N-bis(2-chloroethyl
Amino]-3-fluoropyridine hydrochloride The diol product of Step A (800 m9, 4.0 mmol) is added to 10 m1 of thionyl chloride cooled to about 5°C by an ice bath.

The solution was returned to about 20°C and then stirred under reflux for 6 hours. About 40% of unreacted thionyl chloride was removed under reduced pressure.
Remove at °C. Add 10ml of toluene, then approx.
Concentrate under reduced pressure at 0°C.

This step is repeated two more times to completely remove unreacted thionyl chloride from the remaining hydrochloride dichloride. Stage C: 1-
(3-Fluoro-2-pyridinyl) Piperazine Hydrogenmaleate The crude dichloride hydrochloride residue from Step B was
Dissolve in 0 mt of absolute ethanol and add 2.0 mt of anhydrous ammonia.
Saturate at 0°C and heat in a sealed container at about 100°C for 20 hours.

After concentration under reduced pressure at about 40-45°C, the product is extracted with toluene. Wash this toluene extract with saturated saline,
Dry over anhydrous sodium sulfate, filter overnight, and concentrate to an oil. Add this oil to silica gel 60 (230-400 mesh)
chromatography, eluting with a mixture of 5% methanol and 95% chloroform saturated with ammonia, and conversion to the hydrogen maleate salt with 1 equivalent of maleic acid in ethanol-ethyl acetate. Example 8 Binding test of 1-(3-fluoro-2-pyridyl)piperazine and related compounds to adrenergic receptors α1- and α2-adrenergic receptor binding was
-pyridyl)piperazine and several other structurally related compounds shown in Table 1.

The degree of binding to α1-adrenergic receptors is
Ngrass and Bremrler, Eur'. J. P
harmacOl. 55, 323 (1979), and is designated as K1 in Table 1.

Ki represents the affinity of each compound for the [3H]prazosin binding site in the calf cerebral cortex. α2-
Binding to adrenergic receptors is LyOn and RarKl
all,LlfeSciences26,ll2l(1
980), and similarly Table 1 (7) Ki
It is expressed as

This value indicates the affinity of each compound for the 2[3H]clonidine binding site in the calf cerebral cortex. Table 1 Binding of 1-(3-halo 2-pyridinyl)piperazine and related compounds to adrenergic receptor sites Among the tested compounds, the compounds of the present invention (1, 2 and 3), except for compound 5, clearly showed It showed the strongest affinity for α2-adrenergic receptors and the weakest affinity (highest Ki) for α1-adrenergic receptors.

These compounds of the invention therefore have the greatest selectivity or the highest Kiα1/Kiα2 ratio compared to other tested compounds. Example 9 Active ingredients, starch and magnesium stearate are mixed together.

This mixture is used to fill suitably sized hard shell capsules so that the total weight of the capsule is 100 m9. Example 10 Active ingredients, starch and magnesium stearate are mixed together.

This mixture is used to fill suitably sized hard shell capsules so that the total weight of the capsule is 100 m9. Mix together the active ingredients, starch and magnesium stearate.

Claims (1)

[Claims] Compounds 1-(3-
halo-2-pyridinyl)piperazine or a pharmaceutically acceptable salt thereof. 2 1-(3-fluoro-2-pyridinyl)piperazine or a pharmaceutically acceptable salt thereof Claim 1
Compounds described in Section. 3 2-Y-3-halopyridine (Y is halogen, C_1
Preparation of 1-(3-halo-2-pyridinyl)piperazine (halo is chlorine, bromine or fluorine) by treating with piperazine _-_5alkylsulfonyloxy, benzenesulfonyloxy or toluenesulfonyloxy Method. 4. The method according to claim 3, wherein halo is fluorine and Y is chlorine. 5 An effective amount of 1-( as a pharmaceutical carrier and antidepressant)
3-halo-2-pyridinyl)piperazine (halo is chlorine,
bromine or fluorine) or a pharmaceutically acceptable salt thereof. 6. The antidepressant according to claim 1, wherein the compound is 1-(3-fluoro-2-pyridinyl)piperazine or a pharmaceutically acceptable salt thereof.